Antitumor Activities of a Novel 9‐Aminoanthracycline (SM‐5887) against Mouse Experimental Tumors and Human Tumor Xenografts

Morisada, Shinya; Yanagi, Yoshikazu; Noguchi, Toshihiro; Kashiwazaki, Yasuo; Fukui, Masayoshi

doi:10.1111/j.1349-7006.1989.tb02247.x

Cited by 79 publications

(63 citation statements)

References 5 publications

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“…The AUC values of amrubicinol and amrubicin were calculated by summing trapezoids. The in vivo antitumor activity is expressed as the value of minimal T/C%, from the data of Morisada et al 2) indicates the value for each indicated cell line. R is the correlation coefficient.…”

Section: Resultsmentioning

confidence: 99%

In vivo Efficacy and Tumor‐selective Metabolism of Amrubicin to Its Active Metabolite

Noguchi¹,

Ichii²,

Morisada³

et al. 1998

Japanese Journal of Cancer Research

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The tissue distribution of a novel antitumor anthracycline antibiotic, amrubicin, was studied using seven human tumor xenografts implanted into nude mice, in order to identify the principal factors determining its therapeutic efficacy. We found a good correlation between the level of the metabolite amrubicinol in the tumor and the in vivo efficacy. High metabolic activity of amrubicin to amrubicinol was detected in tumor tissue homogenates, especially in cell lines highly sensitive to amrubicin in vivo. In contrast to amrubicin, the administration of amrubicinol showed less tumorselective toxicity in these human tumor xenograft models. These data indicate that the tumorselective metabolism of amrubicin to amrubicinol resulted in a tumor-selective disposition of amrubicinol, leading to good efficacy in in vivo experimental therapeutic models.

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Section: Resultsmentioning

confidence: 99%

In vivo Efficacy and Tumor‐selective Metabolism of Amrubicin to Its Active Metabolite

Noguchi¹,

Ichii²,

Morisada³

et al. 1998

Japanese Journal of Cancer Research

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“…2) Amrubicinol, which was found in plasma, normal tissues, and tumor tissues of mice treated with amrubicin, was shown to be much more effective than amrubicin on various human tumor cells in vitro. Moreover, amrubicin was metabolized to amrubicinol in some of the human tumor cell lines, and amrubicinol had a higher activity level inside the cells compared to amrubicin.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Amrubicin, a Novel 9‐Aminoanthracycline, and Its Active Metabolite Amrubicinol on Human Tumor Cells

Yamaoka¹,

Hanada²,

Ichii³

et al. 1998

Japanese Journal of Cancer Research

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Amrubicin, a completely synthetic 9-aminoanthracycline derivative, was previously shown to have potent antitumor activities against various human tumor xenografts. In this study, the in vitro activities of amrubicin and its major metabolite, amrubicinol, were examined using 17 human tumor cell lines. Amrubicinol was 5 to 54 times more potent than amrubicin, and as potent as doxorubicin, in inhibiting the growth of the cells following 3-day continuous drug exposure. Amrubicinol closely resembled doxorubicin in its profile of activities on the 17 human tumor cell lines. Cells were incubated with the drugs for 1 h, and the intracellular drug concentration and cell growth inhibition after 3 days were determined. Amrubicinol attained similar intracellular concentrations at lower medium concentrations compared to amrubicin, and the intracellular concentration of amrubicinol necessary to produce 50% cell growth inhibition was 3 to 8 times lower than that of amrubicin in 4 cell lines tested. Amrubicinol has a higher activity level inside the cells than does amrubicin. When cells were incubated with amrubicin for 5 h, a substantial amount of amrubicinol, more than 9% of that of amrubicin, was found in cells in 4 of the 8 cell lines tested. Amrubicinol may contribute to the in vitro growth-inhibitory effect of amrubicin on these cells. The results suggest that amrubicinol plays an important role in the in vivo antitumor effect of amrubicin as an active metabolite.Key words: Anthracycline -Amrubicin -SM-5887 -Metabolism Amrubicin hydrochloride, (+)-(7S,9S)-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione hydrochloride (SM-5887), is a completely synthetic 9-aminoanthracycline derivative.1) It has potent antitumor activities against various human tumor xenografts, being more potent than doxorubicin.2) In contrast to its potent in vivo antitumor activities, the in vitro growth-inhibitory activities of amrubicin were more than 5 times lower than those of doxorubicin in several human tumor cell lines.3)The dissociation between the in vitro and in vivo activities suggests that amrubicin is converted in vivo to metabolites which are more effective cell growth inhibitors than the parent compound. To test this possibility, the growthinhibitory activities of the metabolites of amrubicin were examined using various human tumor cell lines.A major pathway of anthracycline metabolism is known to be the reduction of the C-13 carbonyl group to a hydroxyl group by cytoplasmic carbonyl reductase, and another involves the reductive cleavage of the glycosidic bond between the amino sugar and the chromophore by microsomal glycosidases.4) The C-13 hydroxy derivatives and aglycones of doxorubicin, epirubicin, daunorubicin and idarubicin were found in the plasma of cancer patients, [5][6][7][8] as well as in the plasma and tissues of experimental animals treated with these drugs.9-11) These metabolites were also formed in vitro in human hepatocytes and human tumor cells. [12][13][...

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“…Decomposition of an excess amount of 3 under the reaction conditions produced the undesired by-products. We then turned our attention to acylation of 3 with phthal oyl chloride (2). The yield and the purity of the product (4) were found to depend markedly on the ratio of the reagents.…”

Section: Resultsmentioning

confidence: 99%

14C-Labeling of a Novel 9-Aminoanthracycline.

Nishioka¹,

Fujimoto²,

Kanamaru³

1996

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Antitumor Activities of a Novel 9‐Aminoanthracycline (SM‐5887) against Mouse Experimental Tumors and Human Tumor Xenografts

Cited by 79 publications

References 5 publications

In vivo Efficacy and Tumor‐selective Metabolism of Amrubicin to Its Active Metabolite

In vivo Efficacy and Tumor‐selective Metabolism of Amrubicin to Its Active Metabolite

Cytotoxicity of Amrubicin, a Novel 9‐Aminoanthracycline, and Its Active Metabolite Amrubicinol on Human Tumor Cells

14C-Labeling of a Novel 9-Aminoanthracycline.

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